DESCRIPTION (provided by investigator): In the normal immune system, a fine balance between lymphocyte proliferation on the one hand, and apoptosis, on the other, assures right sizing of the peripheral pool of lymphocytes. Perturbation of this balance could result in immunopathology, as illustrated by certain experimental animal models and human diseases involving immunodeficiency or autoimmunity. This research proposal implicates a novel paradigm of MHC - associated immunopathology. The underlying hypothesis of the proposed research is that a class II MHC - associated defect in death signaling may lead to disproportionate expansion of certain lymphocyte subpopulations in genetically susceptible individuals. Those expanded lymphocyte subsets may allow the emergence of autoimmune lymphocyte clones in some individuals, with resultant autoimmune disease. This hypothesis is based on recent preliminary data showing an HLADRB 1-associated impairment of protein kinase A (PKA)-mediated signaling that may be involved in the expansion of an otherwise rare T cell subset, the CD4+, CD45RO+. CD7- subpopulation of alpha beta T cells. This subset has been shown to be necessary for the expansion of another, normally minor, subset of peripheral T cells, Vgamma9/Vdelta2 cells. It is intriguing that these two subsets have been previously shown to co-accumulate in autoimmune states. In order to investigate the mechanisms involved in the expansion of these T cell subsets, experiments are proposed to further define the chemical composition of PKA signal-inducing ligands and identify the peripheral blood subset of cells unresponsive to those ligands. Additionally, the inhibitory role of nitric oxide on PKA signaling and its involvement in the resistance to apoptosis will be examined. The mechanism contributing to the aberrant PKA signaling pathway in resistant cells will be characterized. Finally, the role of heat shock protein (HSP) 60, as a target cell molecule recognized by the cytolytic cells will be investigated. These studies will examine a novel paradigm relevant to a physiologic regulatory mechanism in the immune system, whose perturbation may set the stage for immunopathology.